Simpson M G, Horner S A, Mistry P, Duffel S, Widdowson P S, Scanlon Y, Lock E A
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK104TJ, UK.
Neurotoxicology. 2005 Jan;26(1):125-32. doi: 10.1016/j.neuro.2004.07.006.
The herbicide cycloate (carbamothioic acid, ethyl(cyclohexyl)-S-ethyl ester) given as a single oral dose to rats, caused selective neuronal cell death in two regions in the rat forebrain, the pyramidal neurons of layers II-III throughout the pyriform cortex and in granule cells of the caudal ventro-lateral dentate gyrus. Male Alderley Park rats, 6-8-week-old, were given a single oral dose of either 0 or 2000 mg/kg cycloate and killed for neuropathological investigation 1, 2, 3, 7, 14 or 28 days after dosing, using a regime of perfusion fixation with modified Karnovsky's fixative, followed by routine paraffin embedding. Seven transverse levels of brain were examined from each rat. Cycloate-induced neuronal cell death was seen in the pyriform cortex 1 day after dosing and persisted through to Day 28, the lesion was more marked in the rostral compared to the caudal region of the pyriform cortex. Neuronal cell death was also observed in the ventro-lateral caudal dentate gyrus on Days 1-14, day after dosing. In the early stages, Days 1-3 and to a lesser extent Day 7, the neuronal cell death resembled apoptosis, characterized by condensation of nuclear material, cell shrinkage and strong cytoplasmic eosinophilia. By Days 14 and 28 and to a lesser extent Day 7, the cell death resembled necrosis, i.e. karyorrhectic nuclei with pale irregular cytoplasm. Microglial accumulation was associated with the neuronal cell injury. In control brains, an occasional apoptotic body was seen in both the pyriform cortex and dentate gyrus. Our results demonstrate that cycloate is a novel neurotoxicant, which following a single large oral dose induces a cell specific and highly localized forebrain lesion. The time course data analyzed temporally, suggests that cycloate may cause an up regulation of apoptosis in selected regions of the adult brain.
给大鼠单次口服除草剂环草敌（乙基（环己基）-S-乙酯氨基硫代甲酸酯）后，在大鼠前脑的两个区域引起选择性神经元细胞死亡，即整个梨状皮质II-III层的锥体细胞以及尾侧腹外侧齿状回的颗粒细胞。给6-8周龄的雄性奥尔德利公园大鼠单次口服0或2000 mg/kg环草敌，给药后1、2、3、7、14或28天处死进行神经病理学研究，采用改良的卡诺夫斯基固定液灌注固定，随后进行常规石蜡包埋。检查每只大鼠脑的七个横切面。给药后1天在梨状皮质可见环草敌诱导的神经元细胞死亡，并持续至第28天，梨状皮质前部的病变比后部更明显。给药后第1-14天，在尾侧腹外侧齿状回也观察到神经元细胞死亡。在早期，即第1-3天以及程度较轻的第7天，神经元细胞死亡类似于凋亡，其特征为核物质凝聚、细胞萎缩和强烈的细胞质嗜酸性。到第14天和第28天以及程度较轻的第7天，细胞死亡类似于坏死，即核碎裂且细胞质苍白不规则。小胶质细胞聚集与神经元细胞损伤相关。在对照脑中，在梨状皮质和齿状回均偶尔可见凋亡小体。我们的结果表明，环草敌是一种新型神经毒物，单次大剂量口服后可诱导细胞特异性且高度局限的前脑损伤。对时间进程数据分析表明，环草敌可能导致成年大脑特定区域的凋亡上调。
